Abnormal blood cholesterol levels increase an individual's risk of coronary heart disease. Cholesterol is transported in the body largely through the interaction of the lipoproteins. A great deal of attention has focused on the search for agents that safely and effectively reduce levels of lipoprotein and thus cholesterol in the blood. While blood cholesterol levels can be somewhat reduced through diet modifications, recourse to drug therapy is often required.
Coronary heart disease (CHD) is caused by atherosclerosis which results from the formation of atherosclerotic plaques or lesions. These plaques are build-ups of cholesterol deposited in the arterial wall. The build-up occurs because cholesterol is insoluble in water and thus is not readily removed by the blood. "If cholesterol is to be transported safely in blood, its concentration must be kept low and its tendency to escape from the bloodstream must be controlled." M. S. Brown and J. L. Goldstein, Science, 232:34-47 (1986).
Initially, free cholesterol is bound to the surface of high-density lipoproteins (HDL) and coupled to a fatty acid in an esterification reaction. The cholesteryl esters which are formed on the surface of HDL are subsequently encapsulated within low-density lipoproteins (LDL). The cholesteryl ester-containing LDL then enters certain cells through a lipoprotein-specific receptor-mediated-endocytosis. Once inside the cell, the esters are hydrolyzed back to cholesterol and put to constructive use in the formation of steroids and membranes, or it is biochemically modified for safe and efficient removal from the body.
Significantly above average levels of HDL have been associated with reduced risk of CHD, while significantly above average levels of LDL have been associated with increased risk of CHD.
The LDL is the most abundant cholesterol-carrying lipoprotein in the human body and carries about three-fourths of the total cholesterol of normal human plasma. Lowering plasma LDL levels will effect a reduction of serum cholesterol and so decrease the progression of atherosclerosis. Furthermore, because the HDL remove free cholesterol from the plasma and prepare it for encapsulation within the LDL an increased HDL/LDL ratio is generally accepted as representing an improved lipoprotein cholesterol profile.
The importance of maintaining a healthy overall lipoprotein cholesterol profile has recently been made evident. Recent studies suggest that heart disease can strike even individuals having safe levels of total cholesterol if their levels of HDL are low. Thus, not only high levels of LDL, but also low levels of HDL can be very dangerous.